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E27IA021www.antonpaar.com Granulation and Dryingthe Choice of xcipients attersRelevant for:excipients, solid dosage forms, pharma, powder rheology, particle size analysis, BET surface area, density, powder rheology, powder flow, flowability, compactabilitycompressibility So influencethe powder processing and the quality of the final dosage form. The success of multiple step processsuch as tableting and capsule filling mostly depends on instrument parametersand powder handlingin intermediate steps like ranulation(wet, dry)and dryingThis application report examinesthe moisture uptake capacity of the excipients milled and sieved lactose andmethylcellulose in order to estimate their behavior during wet granulation.The same excipients were also tested at different temperatures to reproduce the drying effect. It was IntroductionSolid dosage forms such as granules, tablets, capsules and sachets may not be as appealing as some of the novel drug delivery forms of recent years, but they will remainfar and away the most prevalent dosage form on the market. They consist of mixture of active pharmaceutical ingredients (API) and excipients. he excipient type or the excipients Parameters like surface area, density, particle size and cohesion can be measured withton Paar instruments. Knowing these characteristics provides vital information aboutthe most appropriate excipients to use in order to discharge of the batch at the end of manufacturing.The overview of the principal steps of solid dosage forms manufacturing and the corresponding parameters is presented in igure 1.1FlowabilityGoodflowability ensures the appropriate filling ofcapsules orthe die cavityduring tabletingIn this waydosage formswith the consistentweight and uniform strength can be produced.Themeasurement of E27IA021www.antonpaar.com Figure Schematic overview of principal steps for the manufacturing of solid dosage forms 1.2ompactability and compressibilityn solid dosage form manufacturingthe granulation stephelps toimprovethe compression compactability. Tablets can be formed that remain intact, stable and compact when stressis applied.thecase of capsules, a better compaction during filling guarantees highweight uniformity. In fact, density, porosityand particle size distributionof granules influence theoptimization ofthe packingbefore tablets compaction andin the filled capsule. These characteristics alsocontribute to increasingthe consolidation stress applied during tableting. At the end of thegranulation steptablets with lower porosity and higher tablet strength as well as capsulewith better content uniformitycan be produced.Experimental setupThe analysis conducted in this application report focused on three excipientthat are commonly used in solid dosage forms manufacturing: milled lactose , sievedla

ctoseand methylcellulose(MC)Lactose monohydrate is mostly used as diluent (fillers) in tablets or capsules/sachets filling to increase the weight and improve content uniformity. Methylcelluloseactas binder and contributes to the adhesion between the particles (e.g.API and excipients)The aim of the investigation was to evaluate the suitability of the excipients to wet and dry granulation by reproduction of the wettidifferent humidity conditions and dryingbehavior(e.g.fluidized bed dryer) at different temperatures. The following parameters were measured to characterize the powdersin the raw andconditioned statBulk densityand tapped densityCohesion strength, uconfined yield strength principal stress (consolidationstressSurface area and true density Size andparticle size distribution (PSD)emperature, time and humidityconditions used for the experiments are listed in Table1Ambient conditions°C, 30 Conditioning in climate chamber Moistureuptake60 min, 35at 45/ 65 Drying of sample previously conditioned for min at 85H at 35min, 20at 40 Table Overview of time, temperature and humidity conditions The bulk density, cohesion strength and shear cell measurements were only performed for conditioning at 45 and 85(relative humidity). The surface area and true density weremeasured only for raw materials. struments and results3.1Raw material: beforeand after moisture uptakeBulk density 3.1.1The measurements were performed with aModular Compact Rheometer (MCR) equipped with the powder shear cell(PSC)The measuring cell with a volume of 18.9 ml and the corresponding measuring system PSC43(stainless steel attachment)were used for the testsFigure The resultsare listed in Table E27IA021www.antonpaar.com Figure : Measuring system PSC430 with three different attachments (stainless steel, aluminumTeflon Bulk density (045 kPa) SampleRaw 0,487/ 0,8080,460/ 0,8330,518 / 0,804 0,772/ 0,8130,784 / 0,8380,800 / 0,929 0,373/ 0,4000,359 / 0,3890,350 / 0,380 Table : Bulk density of the excipientsmeasured at 0 and Pa before (Raw) and after moisture uptake(4585 %rH) Figure shows the bulk density curve of the milled lactose in raw (red curve) and wetted (blue curves) condition. Figure Bulk densityof milled lactose curve: ML rawight blue curve: ML 45 %rlue curve: ML 85 %r Tapped density, Hausner Ratio and Carr 3.1.2IndexTapped density was measured using an Autotap. Samples were tappeduntil the volume remainsunchanged. The results are shown iTable SampleTapped density, ρ(g/cm Raw45 %r 0.720.750.70 0.870.870.90 0.410.410.41 Table : Tapped densityof excipients before (Raw) and after moisture uptake(45rH) The Hausner Ratio (HR) and Carr Index (CI) were calculated from the tapped density measurements according to Equations 1 and 2 and are given in Table ���ඃ

5DC60;�������� Equation 1: Hausner Ratio= initial volume and V= final volume. ��������100 Equation 2: Carr Index. V= initial volume and V= final volume. Hausner Ratioo-] and Carr Index [%] SampleRaw HR CI HR CI HR CI 1.731.821.65 1.241.281.26 1.321.361.31 Table Hausner atio and Carr Index calculated from tapped density measurements. Cohesion strength, unconfined yield strength 3.1.3principal stressThe cohesion strength and shear measurements were carried out with an MCR (Modular Compact Rheometer). Two types of powder cells were usedPowder Flow Cell (PFC)Powder Shear Cell (PSC)The main difference between these two measuring cells is that measurements that take place in the PFC can be performed in the stationary in the dynamic state, whereas in the PSC the measurements are carried out in the stationary stateonly Figure : Measuring system PSC4312 with shear cell reelowing powders such as sieved lactose and methylcellulose are ideal samples for measurements in the Flow Cell and cohesive powderssuch as milled lactoseare well suitedformeasurements in the Shear Celligure 4)Due toitscohesiveness,milled lactose could not befully fluidized up to a maximum air flow of 15 l/min in the flow cell.Therefore, only the cohesion E27IA021www.antonpaar.com strength of sieved lactose and methylcellulose were measured in the flow cell (Table 5).Sample Fluidization rate [l/min]Cohesion strength [Pa] Raw SL (2.5) C (2) Table : Results of cohesion strength for sieved lactose (SL) and methylcellulose (MC)before (Raw) and after moisture uptake (45rH) Thcohesion strength measurements of methylcellulose are displayed Figure Figure Cohesion strength measurements of methylcellulose Grey curve: MC rawight blue curve: MC wetted at 45 %r lue curve: MC wetted at 85 %r Some of tresults which can be obtained with the shear cell unconfined yield strength and the principal stress of milled lactose are listed in able ParametersRaw C 4331 5541 6728 1 9033 9936 9659 Table : Unconfined yield strength and principal stress of milled lactosebefore (Raw) after moisture uptake(45rH) measured at 6 Figure shows a clear change in flowability at different humidity levels. Figure : Flowability curve of milled lactose comparing raw and wetted material. ed curve: ML rawight blue curve: ML 45lue curve: ML 85 Surface area and true density3.1.4True density of the raw material was measured usinghelium gas withan Anton Paar UltraPyc 1200e. BET surface area was measured using NOVAtouch instrument with Ngas at 77 K. Samples were dried under vacuum at C for oursprior to the measurement. Because true density and surface area are repo

rted per gram of dry sample, the study of these materials was limited to the untreated raw materialsThe results are shownin Table SampleBETsurface area /g)TrueDensity (g/cm 2.431.55 0.861.54 0.651.26 Table Surface area and true density of raw excipients Particle size distribution3.1.5The particle size distribution of theexcipients was measured by means of laser diffraction in the PSA 1190. he measurements in drydispersionwereperformed in VenturireefallmodesThe Fraunhofer approximation mode was selected. Figure and Table showthe results and the corsponding easurement parameters used for Venturimode Figure Particle size distribution (volume based) ofmilled actose, sieved lactose and methylcellulosemeasurementin Venturimode E27IA021www.antonpaar.com Table Volume weighted Dvaluesmeasured in Venturimode In Figure and Table theresults of freefall measurements are presented. Figure Particle size distribution (volume based) of milled lactose, sieved lactose and methylcellulose measurements in reefallmode Table Volumeweighted Dvalues measured in freefallmode 3.2After dryingThe sampleconditioned at 85 %rH and 35°C for 1were then dried at 40and 80for minutes cf. (Tableand subsequently measuredBulk density3.2.1The same instruments and accessories were used as in the previous rheological measurementsChapter 3.1.1)These results provide information on compressibility and compaction behavior.Table 10gives anoverviewof the resultsBulk density (0kPa) SampleRaw85 %r 0,487/0,8080,518/,8040,452/0,6670,525/0,667 0,7720,8130,800/,9290,740/0,8280,726/0,809 0,373/0,4000,350/,3800,335/0,3650,343/0,375 Table Bulk density of the excipients measured at 0 and 45 Pa before (Raw) , after moisture uptake at 85 %rH and after drying at 40 and 80 °C. The bulk density curve for milled lactose is shown in Figure Figure Bulk density of milled lactose Red curve: ML rawBlue dashed curve: ML at 85ight red curve: ML dried at 40 °Ced dashed curve: ML dried at 80 °C apped density, Hausner Ratio and Carr 3.2.2IndexThe measurements were repeated after drying and the impact of temperature on tapped density(TP)was determined, along with the Hausner Ratio (HR)and Carr Index (CI) Table Sample(g/cm(%) T[°C] 0.730.701.531.45 0.890.891.291.35 0.410.391.351.26 Table Tapped density, HausnRatio, and Carrndex for dried samples. E27IA021www.antonpaar.com Cohesion strength, unconfined yield strength 3.2.3and principal stressThe cohesion strength values of sieved lactose and methylcellulose granules after drying are listed iTable Sample Fluidization rate [l/min]Cohesion strength [Pa] Raw85 %rH SL (2.5) MC (2) Table Results of cohesion strength for sieved lactose (SL) and methylcellulose (MC) before (Raw) , after moisture uptake at 85 %rH and after drying at 40 and 80 °C. Figure displays the coh

esion strength curveof methlcellulose. Figure Cohesion strength measurements of methylcellulose after drying. y curve: MC rawht red curve: MC dried at 40 °C ed curve: MC dried at 80 °C The results of the shear cell for milled lactose granules are displayed in Table 13.ParametersRaw%r [Pa] [Pa] Table : Overview of unconfined yield strength and principal stress measured at 6Pa before (Raw) , after moisture uptake at 85 %rH and after drying at 40 and 80 Particle size distribution3.2.4The measurements were repeated after drying and the impact of temperature on granule formation wastested. Figure shows the particle size distribution measured after drying at 80°C in Venturimode. Table presentthe overviewof measurementsafter drying at °C and 80°C. igure Particle size distribution (volume based) of lactose milled, sieved and methylcellulose measurements in Venturi mode before (Raw) and after dryingat 80 Table Volume weighted Dvalues asured in Venturimode The analysis of agglomerates after drying was done y using the freefall mode. The exemplary particle size distributionwhich wasmeasured in freefall at 80°C is shown in Figure . The overview of all results obtained after 40 and 80°C drying is displayed in Table Figure Particle size distribution (volume based) ofmilled lactosesieved lactose ethylcellulose measurements in reefall after dryingat 80 E27IA021www.antonpaar.com Table Volume weighted Dvalues measuredin freefall Discussion4.1FlowabilityThe effect of moisture uptake and drying on the flowability is discussed in this section.Bulk density4.1.1Looking at the raw excipients, methylcellulose presents the lowest bulkdensity while sieved lactose the highest (able 2).The moisture uptake causes an increase of the bulk density especially for milled and sieved lactose,where the adsorbed water fills the voids between the particles. ethylcellulose stays rather constant able 2).After drying, the most relevant changes can be observed for milled lactoseable 10Figure . The bulk density increase at kPa is related to granuleformation the decrease of bulk density at 45kPa is determined by the granule internal porosity that will favor the compactabilityand the compressibility(see paragraph 4.2.1Hausner Ratio and Carr Index4.1.2Table 16 shows the scale of flowability according to the usnerRatio and the Carr IndexHausner RatioCarr Index (%)Flow Character 1.11Excellent 1.121.18Good 1.191.25Fair 1.261.34Passable 1.351.45Poor 1.461.59Very poor �1.6�38Very, very Table : Scale of flowability (1) . Raw excipients have different flowabilityMilled lactose Poorflowabilityieved lactose and methylcelluloseairand assableflowability, respectivelyable). or the milled lactosethe value of the Hausner Ratio and Carr Index increases after 45%rH and decreases after cond

itioning at 85able 4).low rH,the liquid bridges workas sintering medium between the particles and increase the cohesion. Therefore, the flowability decreases. At higher H, such as 85%rH, the excess water starts to dissolve the powder and acts as a lubricantslightly improving the flowabilityFor the sieved lactose,the value of the Hausner Ratio and Carr Index shows a slight increase for both values in comparison to the starting materialableThis indicates that water may contributethe interparticles adhesionFor the methylcellulosean increase of both parameters after 45%rwas discovered,but after they decrease and reach a value close to the starting materialable 4), indicatingthat methylcellulose,after conditioninghas still passable flowability.After dryingat 80significant improvement of flowabilityfor the milled lactose, a slight change for the methylcellulose and adecrease of flowability forsieved lactoseable 11)was observedThese data confirthat wet granulationof methylcellulose and sieved lactosewould nothave any additional advantage in terms ofthe flowabilitCohesion strength, unconfined yield strength 4.1.3and principal stressSieved lactose and methylcellulose present a moderate cohesiveness in raw conditionable 5) while milled lactose is very cohesive (igureTable6).Sieved lactose undergoes an increase of the cohesion strength after 45%rH and a decrease after %rable 5). Thisauses a flowability changewhich can also be observed by the Hausner Ratio and Carr Index.Methylcelluloseshows adecrease of cohesion strength and preserves a good flowabilityigure 5able 5The cohesionof milled lactose continues to increase after wettingas indicated by the high value of theunconfined yield strength able6). After drying, the cohesion strength of sieved lactose granules increases while methylcellulose granules aresimilar to the raw materialigure able 12).follows that there is no improvement of flowability for sieved lactose. Thisis confirmed by the change of particle sizeSection4.1.5)as well as by the Hausner Ratio and Carrvaluesilled lactosegranuleseven with an increase in flowability (Hausner Ratio E27IA021www.antonpaar.com Carr Index, particle size), arestill cohesive. In fact, the unconfined yield strength increases (able 13) whichindicates a higher resistance tcrackingof granuleswhen the moldused for the tablet press is removedFigure 1shows an example of the unconfined yield strength and the principal stressas would be acquired through a uniaxial test Figure Example of the principal stress (on the left and unconfined yield strength () on the right Surface area and true density4.1.4In the case of low intraparticle porosity materials, such as those in this study, there is a direct correlation between surface area and particle size: The smaller the particle size, the larger the

surface area(section 4.1.5). This correlation holds for the materials studied, where BET surface area of the lactose milled lactose sieved methylcellulose The porosity percentage can be calculated from the bulk density and true density by employing Equation 3. In the case of the samples studied, porosity is primarily interparticle porosity, as the low surface areas indicate a lack of pores insidethese materialsAccording to the equation, milled lactoseraw shows a higher interparticleporosity andthisdecreases the flowability and the particle packingPorosity can be also relatedto the low bulk densitythe small particle size and high cohesion.�������������������������� 100 Equation 3: Calculation of porosity from bulk and true densities Particle size and particle size distribution4.1.5The powder hygroscopicity affectsthe behavior during wet granulation and the tendency to water loss during drying. The investigation of the particle size distribution enables one to monitor the size enlargement due to water uptake check the granule formation and the granule size after drying.In this way, powder agglomeration can be controlledto investigate possible caking and define the impact on flowability(2)Among the tested excipients in the raw state, milled lactose shows the smallest size with a D50 of 28.5 µm able 8), meaning that the surface area available for water adsorption is largeras indicated by the measured values (able 7Due to this, the size increase of primary particles igure ableandagglomerates (Figure able is more consistent for milled lactose. The Dvalue,[4,3] which is the volume weighted mean sensitive to change in the coarse fraction, increases while passing from the raw conditionto 65H but decreases when the moisture goes up to 85able8, 9). In fact, at oderateH such as 45and H, water molecules are adsorbed onto the particle surface and can form liquid bridges between particles. At this stage, due to liquid bridges, the size increase is consistent but the adhesion caused by the entrapped water reduces the flowability as is confirmed by the values of the Hausner Ratio and Carr Index. y increasing the , an event called deliquescence occurs milledlactose. The particles start to dissolve in the waterand therefore, the particle size of the solid fraction startto decrease(2)For sieved lactose primary particles and agglomerates able8, 9) show an increase of the Dvalue[4,3] because liquid bridges start to build interconnections between the particles. The adhesion forces causeslight decreas

e offlowability as is confirmed by the Hausneratioand Carr IndexvaluesAs regards the methylcellulose, the particle size increase starts to be significant after 85%rtreatment Tables8, 9). However, the water acts as a lubricant and because ofparticle sizeand adsorbed water, the excipient preserves a good flowability.This is also confirmed by the Haner Ratio and Carr Index values as well asby the moderatecohesion strength.After drying, granules are formed due to removal of water and the consolidationof particle interconnections through the creation osolid bridges.The primary particles of milled lactose show a consistent increase in size after drying (igure 11Table ) and the formation of granules is confirmed by the size of agglomerateswith a D50 of 257.1 µm after 40°C and 233.4 µm after 80igure 12Table ). Therefore,the flowability of the powder is better than the raw material, as indicated by the HausneRatio and Carr IndexvaluesFor sieved lactose, the size increase of primary particles suggests that solid bridges are formed which keep the particles together and promote their granulation (igure Table ). oweverTable shows that after drying at 80the size of agglomerates (D50154.2µm) is close to that of agglomerates measured after 85%r(D50166.6µm).This couldmean that after the dryingstep,the water was not completely removedand thiscould be an issue in wet granulation. The final flowability after wetting and drying is less than the raw materials, as is shown by the results of HausnerRatio E27IA021www.antonpaar.com and Carr Index calculations the increase of the cohesion strength.Formethycellulose, the results show thatafter drying, the excipient retainsthe same structural properties of its raw materials. In fact, the particle size distribution of the raw material overlapthe one measured after drying (igure). This confirms the outcomes the cohesion strength, Hausner Ratio Carrndexcalculations4.2ompactability and compressibilityThe following discussion is focused on the capacity of formed granules tocompact and compress.Bulk densityand peddensity4.2.1The filling capacity of a capsule ora sachet as well as the tablet strength before cracking can be estimated by measuring the bulk density and the tapped density of raw materials as well as of final granules.In the case of the investigated excipients, milled lactosegranulesat the end of the drying processshowat 45kPalow bulk density while sieved lactose and methylcellulose do not have consistent changesin comparison with the raw materialsble 10, igure ). However, the low bulk density of granules formed by milled lactose and methylcellulosewill improve the compressionduring tableting as well as the packingin capsule filling. In fact, a lower bulk density is linked to an increased porosity of granules(3). Because of thi

s, they will undergo a plastic deformation under compression, which increases the area of contact between particles(3; 4). At the end, tabletwith lower porosity and higher tensile strength are produced. In the case of capsules, the voids can be filled by excipient or API of smaller size and the packing density can be improved, as well as the content uniformity (4)The results of the tapped density for thethree excipients did notshow significant differences after and before conditioningTablesNonetheless, sieved lactose shows a high tapped density, meaning that this excipient could be used to produce tablets with high tensile strength by means of direct compression or to improve the granule packing in the capsule filling process.Cohesion strength and consolidationstress4.2.2The good flowabilityable 4)and the moderate cohesion strengthable 5)of raw sieved lactose and raw methylcelluloseke them suitable for dry granulation and direct compressionIn fact, the results obtained in thisanalysisTables 12, 13)ow that wet granulation would notfavor the flowabilitySection4.1)or compressibilityof these excipients. This is also confirmed by the bulk density, particle size change, Hausner Ratio and Carr Indexcalculationsontrary, after moisture uptake and consecutive drying, the principal stressof milled lactosegranulesincreasesable 13), indicatingthat the stressthat can be applied during tabletingor capsule filling can be increased without causing granule breakageSurface area4.2.3The high surface area of milled lactoseable 7) and therefore the higher interparticulate interactionsmakes challengingthe compactabilityor compression without wet granulation. Due tothe low surface areaand therefore, to the low attrition forces between particlesraw sieved lactose and raw methylcellulose are more suitable for dry granulation and direct compression.Particle size andarticle size distribution4.2.4Compressibility as well as compaction improvewith increased particle size and decreases as the size becomes smaller. In fact, small particles have higher surface area and therefore, higher frictions. Because of this, they havess ability to lock together as it is explained in Section 4.2.3.According tothe results for the three excipientsin this analysis, the granulation process could contributesuccessfullyto the size increaof milled lactoseFigures11, 12Sieved lactosedoes not require wet granulation because the size of the starting powder is already promising for thecompressibility.Nonetheless, due tolowcohesion strengththe combination with a binder excipient having a broader particle size distribion would enhance the strength of final tablets.It follows that sieved lactosea useful excipient in the direct compression processor in capsule filling. This is alsoconfirmed by its densitycohesionand raw su

rface area. The size increaseof methylcellulosein the wet granulation processis notsignificantas shown by the results of this analysisThe raw material hasdisplays a distinct affinity for compressibility due todiscretecompressibility due to the broader particle size distribution andthe moderate cohesion strength.For this reason, it can be used in the dry granulation and direct compression processbinder, mixed with other excipients such as sieved lactose.ConclusionsAs demonstrated by the results of this analysis, the raw excipientshave different flowabilityand compressibility that can be influencedby granulation.Cohesion strength, Hausner RatioCarr Index, bulk density, particle size distribution and surface areavaluesshow that milled lactose is a cohesive, poor E27IA021www.antonpaar.com flowing powder while sieved lactose and methylcellulose are powderswith medium flowabilityHowever, the time, drying temperatureand relative humidity have a different impact on handling and processingof excipientsThe moisture uptakeis faster and more significant for milled lactoseand the granules formed after drying at high temperature show a better flowability and compressibility than the raw material. The wetting and consecutive drying process negatively impactthe sieved lactose flowability.The increaseof drying temperature does not have any benefit on granule formation. Water is not completely moved after drying andthe wet granulwould resultfragilesolid dosageforms. Therefore, sieved lactose would be more suitable as diluent in the direct compression process or in capsule filling.Methylcellulose preserves its flowability and compressibility after conditioning. The parameter changes due tomoisture and temperatureare reversibe, indicating that methylcellulosewould be more appropriate as binderin combinationwith other excipients in dry granulation or direct compression.The results of this analysis demonstrate that the choice of excipients and process parameters (temperature, relative humidity, timecan be definedand improved during the manufacturing steps before final dosage forms are produced.References1. Pharmacopeia, U.S1174 Powder Flow. 2002.2. How does particle size influence caking in lactose powder?M. Carpin, H. Bertelsen, A. Dalberg, J.K. Bech, J. Risbo, P. Schuck, R. Jeantet2017.3. A compressibility and compactibility study of real tableting mixtures: The effect of granule particle sizeajaantlIlija Ili, Franc Vrecer, and SaBaumgartner20124. Physical Processes of TabletingE. N. Hienstandx, J. E. Wells, C. B. Peot, and J. F. Ochs, 1977.5. Effects of powder flow properties on capsule filling weight uniformityOsorio, JMuzzio, Fernando2013.Contact Anton Paar GmbHTel: +43 316 257rheoapplication@antonpaar.comapplication@antonpaar.comapplication@antonpaar.comWeb: www.antonpaar.com